Reprogramming tumor-associated macrophages to outcompete endovascular endothelial progenitor cells and suppress tumor neoangiogenesis

• DOI: 10.1016/j.immuni.2023.10.010
• Publication Date: 2023-11-14T16:36:50Z
• Authors: Mytrang H. Do; Wei Shi; Liangliang Ji; Erik Ladewig; Xian Zhang; Raghvendra M. Sri...; Kristelle J. Capi...; Chaucie Edwards; Isha Malik; Briana G. Nixon; Efstathios G. Sta...; Ming Liu; Shun Li; Peng Li; Chun Chou; Ke Xu; Ting-Wei Hsu; Xinxin Wang; Timothy A. Chan; Christina S. Leslie; Ming O. Li
• Keywords: Mammals; Neovascularization, Pathologic; Tumor Suppressor Proteins; TOR Serine-Threonine Kinases; Tumor-Associated Macrophages; Animals; Humans; Endothelial Protein C Receptor; Mechanistic Target of Rapamycin Complex 1; Tuberous Sclerosis Complex 1 Protein; 3. Good health; Endothelial Progenitor Cells

Tumors develop by invoking a supportive environment characterized by aberrant angiogenesis and infiltration of tumor-associated macrophages (TAMs). In a transgenic model of breast cancer, we found that TAMs localized to the tumor parenchyma and were smaller than mammary tissue macrophages. TAMs had low activity of the metabolic regulator mammalian/mechanistic target of rapamycin complex 1 (mTORC1), and depletion of negative regulator of mTORC1 signaling, tuberous sclerosis complex 1 (TSC1), in TAMs inhibited tumor growth in a manner independent of adaptive lymphocytes. Whereas wild-type TAMs exhibited inflammatory and angiogenic gene expression profiles, TSC1-deficient TAMs had a pro-resolving phenotype. TSC1-deficient TAMs relocated to a perivascular niche, depleted protein C receptor (PROCR)-expressing endovascular endothelial progenitor cells, and rectified the hyperpermeable blood vasculature, causing tumor tissue hypoxia and cancer cell death. TSC1-deficient TAMs were metabolically active and effectively eliminated PROCR-expressing endothelial cells in cell competition experiments. Thus, TAMs exhibit a TSC1-dependent mTORC1-low state, and increasing mTORC1 signaling promotes a pro-resolving state that suppresses tumor growth, defining an innate immune tumor suppression pathway that may be exploited for cancer immunotherapy.